Centrally acting adrenomedullin in the long‐term potentiation of sympathetic vasoconstrictor activity induced by intermittent hypoxia in rats

Abstract

New Findings What is the central question of this study?Adrenomedullin in the rostral ventrolateral medulla (RVLM) increases sympathetic activity; given that adrenomedullin is released during hypoxia, what are the effects of its agonism and antagonism in the RVLM after chronic intermitent hypoxia (CIH) exposure? What is the main finding and its importance?CIH exposure sensitizes adrenomedullin‐dependent mechanisms in the RVLM, supporting its role as a sympathoexcitatory neuromodulator. A novel mechanism was identified for the generation of sympathetic overdrive and hypertension associated with hypoxia, providing potential guidance on new therapeutic approaches for controlling sympathetic hyperactivity in diseases such as sleep apnoea and neurogenic hypertension. Abstract Adrenomedullin in the rostral ventrolateral medulla (RVLM) has been shown to increase sympathetic activity whereas the antagonism of its receptors inhibited this autonomic activity lowering blood pressure in conditions of hypertension. Given that hypoxia is a stimulant for releasing adrenomedullin, we hypothesized that the presence of this peptide in the RVLM associated with chronic intermittent hypoxia (CIH) would cause sympathetic overdrive. Juvenile male rats (50–55 g) submitted to CIH (6% oxygen every 9 min, 8 h day−1 for 10 days) were studied in an arterially perfused in situ preparation where sympathetic activity was recorded. In control rats (n = 6), exogenously applied adrenomedullin in the RVLM raised baseline sympathetic activity when combined with episodic activation of peripheral chemoreceptors (KCN 0.05%, 5 times every 5 min). This sympathoexcitatory response was markedly amplified in rats previously exposed to CIH (n = 6). The antagonism of adrenomedullin receptors in the RVLM caused a significant reduction in sympathetic activity in the CIH group (n = 7), but not in controls (n = 8). The transient reflex‐evoked sympathoexcitatory response to peripheral chemoreceptor stimulation was not affected by either adrenomedullin or adrenomedullin receptor antagonism in the RVLM of control and CIH rats. Our findings indicate that CIH sensitizes the sympathoexcitatory networks within the RVLM to adrenomedullin, supporting its role as an excitatory neuromodulator when intermittent hypoxia is present. These data reveal novel state‐dependent mechanistic insights into the generation of sympathetic overdrive and provide potential guidance on possible unique approaches for controlling sympathetic discharge in diseases such as sleep apnoea and neurogenic hypertension.

Active expiration and chronic intermittent hypoxia‐induced hypertension: A hypothesis that still breathes!

“…It is also important to note that a change in respiratory–sympathetic coupling in intact rats exposed to CIH seems to be only one of several mechanisms contributing to sympathetic overactivity and hypertension. In another recent study, we documented that bilateral microinjection of adrenomedullin into the RVLM produced long‐lasting sympathetic nerve activation throughout the respiratory cycle (Zoccal et al., ). In the same study, bilateral adrenomedullin receptor antagonism in the RVLM reduced the expiratory‐related sympathetic overactivity in rats exposed to CIH.…”

Brainstem adrenomedullin facilitates intermittent hypoxia‐induced hypertension: A sympathetic story of a selfish brain

“…Although it is likely that there are multi‐site contributors to CIH‐induced hypertension relevant to obstructive sleep anoea, Zoccal et al. () provide a new and important link between CIH‐induced peripheral chemoreceptor activation and brainstem adrenomedullin as combined drivers of sympathetic nervous overactivity underpinning high blood pressure. Although there is urgency in the need for effective anti‐hypertensive strategies in sleep apnoea and other forms of neurogenic hypertension, one is left to ponder the potential consequences of stealing supply from the selfish brain.…”

“…In the September issue of Experimental Physiology , Zoccal et al. () explore whether centrally acting adrenomedullin is implicated in the persistent sympathetic nervous hyperactivity that is characteristic of animal models of CIH and human sleep apnoea and that is considered causal to the development of high blood pressure. Adrenomedullin is a multifunctional vasoactive peptide member of the calcitonin gene‐related peptide family of hormones (Schönauer, Els‐Heindl, & Beck‐Sickinger, ).…”

“…Zoccal et al. () draw focus to the selfish brain theory, suggesting that brainstem hypoxia triggers systemic hypertension that facilitates increased cerebral blood flow, hence oxygen supply, at the expense of the long‐term pathophysiological consequences of high blood pressure. Exposure to repeated bouts of hypoxia or perhaps persistent central hypoxia after exposure to CIH, as described recently in the kidney (O'Neill et al., ), evokes adrenomedullin‐dependent sympatho‐excitation in this important translational model.…”

“…Zoccal et al. () used the established working heart–brainstem preparation to record phrenic nerve and thoracic sympathetic nerve activities in sham‐ and CIH‐exposed rats to determine respiratory and autonomic responses to adrenomedullin receptor agonism and antagonism via microinjections into the rostral ventrolateral medulla (RVLM), with and without concomitant repeated peripheral arterial chemoreceptor stimulation using potassium cyanide. In CIH‐exposed rats, baseline sympathetic activity and sympatho‐excitatory responses to peripheral chemoreceptor activation were increased compared with sham‐exposed rats.…”